Chapter 77

IODIDE PUMP—THE SODIUM-IODIDE SYMPORTER (IODIDE TRAPPING)
THYROID
• butterfly-shaped gland below neck and Adam’s apple along front of windpipe
• located immediately below the larynx on each side of and anterior to the trachea
• one of largest of the endocrine glands = weighing 15 to 20 grams in adults
This process occurs as follows:
IODIDE TRAPPING • apical surface of thyroid cells sends out pseudopod extensions
→ first step in thyroid hormone formation
→ transport of iodide from blood into the thyroid glandular cells and follicles • pseudopod extensions close around small portions of colloid
>>> forming Pinocytic Vesicles
• Basal Membrane of Thyroid Cell
→ counts iodide actively to interior of cell through sodium iodide symposium or NIS • Pinocytic Vesicles >>> enter apex of thyroid cell

• secretes two major hormones • one iodide ion comes in along with two sodium ions • Lysosomes fuse with vesicles >>> form digestive vesicles
→ Thyroxine (T4) → contain digestive enzymes from lysosomes ++colloid
→ Triiodothyronine (T3) • energy comes from sodium potassium pumps sodium out of the cell
→ bring in potassium into the cell • Multiple proteases among enzymes
• thyroid gland also secretes Calcitonin = hormone involved in calcium metabolism → digest thyroglobulin molecules +++ release thyroxine and triiodothyronine in free
• Normal gland form
• lack of thyroid secretion = basal metabolic rate falls 40% to 50% below normal → iodide pump concentrates iodide about 30 times its concentration in blood → >>> diffuse through base of the thyroid cell into the surrounding capillaries.
• extreme excesses = increase basal metabolic rate to 60% to 100% above the normal. → thyroid hormones = released into the blood
• Thyroid gland becomes maximally active
SYNTHESIS AND SECRETION OF THE THYROID METABOLIC HORMONES → concentration can rise as high as 250 times rate of iodide trapping • Some of thyroglobulin in colloid enters thyroid cell by ENDOCYTOSIS
→ after binding to megalin
THYROXINE (T4) TRIIODOTHYRONINE (T3) • Thyroid is influenced by several factors
→ most important being concentration of thyroid stimulating hormone • MEGALIN
93% 7% triad of thyroiodin protein located on lumen membrane of cells
• TSH stimulates and hypophysectomy = diminishes activity of iodide pump in thyroid cells
almost all is converted to T3 in tissues • megalin-thyroglobulin complex
4x as potent as Thyroxine
• Iodide is transported out of thyroid cells across apical membrane into follicle → carried across cell by transcytosis to basolateral membrane
→ by chloride iodide ion counter transporter molecule called PENDRIN → portion of megalin remains bound to thyroglobulin and released into capillary blood
present in blood in much smaller quantities and
persists for a much shorter time T3 AND CHEMISTRY OF T4 AND TRIIODOTHYRONINE FORMATION • ~three quarters of iodinated tyrosine in thyroglobulin never become thyroid hormones
→ but remain monoiodotyrosine and diiodotyrosine
PHYSIOLOGICAL ANATOMY OF THE THYROID GLAND FORMATION AND SECRETION OF THYROGLOBULIN BY THE THYROID CELLS
• thyroid cells are typical protein secreting glandular cells • During digestion of thyroglobulin molecule to cause release of T4 and T3
• large numbers of closed follicles (100 to 300 micrometers in diameter) → iodinated tyrosines are freed from thyroglobulin molecules.
→ filled with secretory substance called colloid • endoplasmic reticulum and Golgi apparatus → not secreted into the blood; iodine is cleaved from them by a deiodinase enzyme
→ lined with cuboidal epithelial cells → synthesize and secrete into follicles a large glycoprotein molecule = thyroglobulin
• Deiodinase Enzyme
• major constituent of colloid = large glycoprotein thyroglobulin • thyroglobulin contains about 70 tyrosine amino acids → makes virtually all iodine available again for recycling within gland
→ contains the thyroid hormones → for forming additional thyroid hormones
• first essential step
• blood flow about five times weight of the gland each minute → conversion of iodide ions to an oxidized form of iodine • congenital absence of deiodinase enzyme
→ situated near Mani capillaries or blood vessels → then capable of combining directly with amino acid tyrosine → person = iodine deficient; failure of this recycling process.

• contains C cells that secrete calcitonin • oxidation of iodine = promoted by enzyme PEROXIDASES
→ contributes to the regulation of plasma calcium ion concentration → compounding hydrogen peroxide
→ provides a system capable of oxidizing iodine
IODINE IS REQUIRED FOR FORMATION OF THYROXINE → either located in apical membrane, the cell or attached to it
• 50 milligrams of ingested iodine in form of iodides are required each year • when peroxidase system is blocked or when it is hereditary absent from the cell
→ about 1 mg/week → rate of formation of the fibroid hormones falls to zero
• common table salt = iodized with ~1 part Na iodide to every 100,000-parts NaCl • After synthesis
→ thyroglobulin molecule contains up to 30 thyroxine and a few thyroid molecules
FATE OF INGESTED IODIDES → amount stored = sufficient to supply body w/ normal reqs of TH for 2-3 months
• absorbed from Gi tract into blood in about the same manner as chlorides
• rapidly excreted by the kidneys RELEASE OF THYROXINE AND TRIIODOTHYRONINE FROM THYROID GLAND
→ 1/5 are selectively removed from circulating blood by cells of thyroid gland • Most of thyroglobulin is not released into circulating blood
→ used for synthesis of the thyroid hormones → thyroxine and triiodothyronine are cleaved from the thyroglobulin molecule
→ these free hormones are released
DAILY RATE OF SECRETION OF THYROXINE AND TRIIODOTHYRONINE
• 93% = THYROXINE
• 7% = TRIIODOTHYRONINE
• one half of the thyroxine is slowly deiodinated to form additional triiodothyronine
• hormone finally delivered to and used by the tissues is mainly triiodothyronine
→ 35 micrograms of triiodothyronine per day
TRANSPORT OF THYROXINE AND TRIIODOTHYRONINE TO TISSUES
• mainly bound to plasma proteins;
→ thyroxin-binding globulin and thyroxine-binding prealbumin albumin
• T3 and T4 = released slowly to tissue cells >>> inside cells they are stored in days/weeks
→ ½ of T4 = released to tissue cells every six days
→ ½ of T3 = 1 day

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PHYSIOLOGICAL FUNCTIONS OF THE THYROID HORMONES EFFECTS OF THYROID HORMONE ON SPECIFIC BODY FUNCTIONS INCREASED HEART RATE
• heart rate sensitive physical signs
THYROID HORMONES INCREASE TRANSCRIPTION OF LARGE NUMBERS OF GENES STIMULATION OF CARBOHYDRATE METABOLISM • used in determining whether patient has excessive or diminished TH production
• rapid glucose uptake by cells
• general effect of TH = activate nuclear transcription of large numbers of genes • enhanced glycolysis INCREASED HEART STRENGTH
• enhanced gluconeogenesis • increased enzymatic activity = increases strength of heart
• result >>> generalized increase in functional activity throughout the body. • increased rate of absorption from GI tract
• increased insulin secretion • heart strength that occurs in mild fevers and during exercise
• more than 90% of thyroid hormone molecules that bind with receptors is triiodothyronine → with its resultant secondary effects on carbohydrate metabolism
• TH increased
• thyroid hormone receptors are either: STIMULATION OF FAT METABOLISM → heart muscle strength may become depressed
→ attached to the DNA genetic strands • mobilizes lipids from fat tissue → because of long-term excessive protein catabolism
→ located in proximity to them → decreasing fat stores in body
→ increasing free fatty acid concentration in the plasma • severely thyrotoxic patients die of cardiac decompensation
• TH + THR = initiate transcript process and forming mRNA → secondary to myocardial failure
EFFECT ON PLASMA AND LIVER FATS → increased cardiac load imposed by increase in cardiac output
THYROID HORMONES INCREASE CELLULAR METABOLIC ACTIVITY • INCREASED TH
→ decreases concentrations of cholesterol, phospholipids, triglycerides in plasma NORMAL ARTERIAL PRESSURE
• basal metabolic rate = increase to 60 to 100 percent above normal → even though it increases the free fatty acids • mean arterial pressure = remains about normal after administration of TH
→ when large quantities of the hormones are secreted → increased blood flow through tissues between heartbeats
• DECREASED TH
• rate of utilization of foods for energy is greatly accelerated. → greatly increases plasma concentrations of cholesterol, phospholipids, triglycerides • pulse pressure = increased
→ almost always cause excessive deposition of fat in liver
TH INCREASE ACTIVE TRANSPORT OF IONS THROUGH CELL MEMBRANES • HYPERTHYROIDISM
• large increase in circulating plasma cholesterol in prolonged hypothyroidism → systolic pressure elevated 10 to 15 mm Hg
Na-K-ATPase → often associated with severe atherosclerosis → diastolic pressure reduced a corresponding amount
• increases its activity in response to thyroid hormone
INCREASED RESPIRATION
• increased activity = increases rate of transport of Na and K ions through cell membranes INCREASED REQUIREMENT FOR VITAMINS • increased rate of metabolism = increases utilization of O2 and formation of CO2
→ process uses energy = increases amount of heat produced in the body • vitamins = essential parts of some of enzymes or coenzymes → activate all mechanisms that increase rate and depth of respiration.
→ might be one of mechanisms by which TH increases body’s metabolic rate → thyroid hormone increases need for vitamins
INCREASED GASTROINTESTINAL MOTILITY
• thyroid hormone causes cell membranes to become leaky to Na ions • relative vitamin deficiency • increased appetite and food intake
→ further activating sodium pump → occur when excess thyroid hormone is secreted
→ further increasing heat production • thyroid hormone increases
→ rates of secretion of the digestive juices
INCREASED BASAL METABOLIC RATE → motility of the gastrointestinal tract
EFFECT OF THYROID HORMONE ON GROWTH • increase the basal metabolic rate 60 to 100 percent above normal
• Hyperthyroidism = results in diarrhea
• effect of TH on growth is manifest mainly in growing children DECREASED BODY WEIGHT • Hypothyroidism = constipation
• greatly increased amount of TH = decreases body weight
Children with Hypothyroidism • greatly decreased amount of TH = increases body weight EXCITATORY EFFECTS ON THE CENTRAL NERVOUS SYSTEM
• rate of growth is greatly retarded • thyroid hormone increases rapidity of cerebration
• effects do not always occur → thought processes may be dissociated
Children with Hyperthyroidism → TH also increases the appetite = counterbalance the change in metabolic rate.
• excessive skeletal growth = child considerably taller at an earlier age • lack of TH decreases rapidity of cerebration
• bones also mature more rapidly EFFECTS ON CARDIOVASCULAR SYSTEM
• epiphyses close at an early age • hyperthyroidism is likely to be:
• duration of growth and the eventual height of adult actually may be shortened INCREASED BLOOD FLOW AND CARDIAC OUTPUT → extremely nervous
• increased in oxygen metabolization and release of metabolic end products from tissues → psychoneurotic tendencies (anxiety complexes, extreme worry, paranoia)
Important Effect of TH → = cause vasodilation in most body tissues = increasing blood flow
• promote growth and development of brain during fetal life and first few years of postnatal EFFECT ON THE FUNCTION OF THE MUSCLES
• rate of blood flow in skin = increases • slight increase in TH = muscles react with vigor
• If fetus does not secrete sufficient quantities of thyroid hormone → because of increased need for heat elimination from the body
→ growth and maturation of brain both before birth and afterward = greatly retarded • quantity becomes excessive = muscles become weakened
→ brain remains smaller than normal • increased blood flow = cardiac output increases → excess protein catabolism
→ rising to 60% or more above normal
→ falling to 50% of normal in severe hypothyroidism • lack of TH = muscles are sluggish and relax slowly after a contraction

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MUSCLE TREMOR REGULATION OF THYROID HORMONE SECRETION FEEDBACK EFFECT OF TH TO DECREASE ANT PITUITARY SECRETION OF TSH
• most characteristic signs of hyperthyroidism = fine muscle tremor
→ not coarse tremor in Parkinson’s disease or when a person shiver TSH (FROM THE ANTERIOR PITUITARY GLAND) INCREASES THYROID SECRETION • increased thyroid hormone in the body fluid
→ occurs at the rapid frequency of 10 to 15 times per second → decreases secretion of TSH by anterior pituitary
• TSH or thyrotropin = anterior pituitary hormone;
• observed easily by placing a sheet of paper on extended fingers → increases thyroid secretion • when rate of hormone secretion rises to about 1.75x times normal
→ noting the degree of vibration of the paper → glycoprotein with molecular weight of about 28,000 → rate of TSH depletion falls essentially 0
→ increases secretion of thyroxine and triiodothyronine by the thyroid gland
• increased reactivity of neuronal synapses in areas of spinal cord that control muscle tone ANTITHYROID SUBSTANCES SUPPRESS THYROID SECRETION
EFFECTS
• important means for assessing degree of thyroid hormone effect on CNS 1. THYROCYANATE
1. Increased proteolysis of the thyroglobulin → decreases iodide trapping
EFFECT ON SLEEP • already been stored in the follicles
• exhausting effect of TH on musculature and CNS • releasing TH into circulating blood and diminishing the follicular substance 2. PROPYLTHYIOURACIL
• hyperthyroidism = constant tiredness → prevents formation of TH from iodides and tyrosine
2. Increased activity of the iodide pump
• excitable effects of TH on synapses = difficulty to sleep • increases rate of “iodide trapping” in glandular cells 3. HIGH CONCENTRATION OF ORGANIC IODIDES
• increasing ratio of intracellular to extracellular iodide concentration in glandular substance → decrease thyroid activity and thyroid gland size
• HYPOTHYROIDISM → as much as eight times normal
→ extreme somnolence DISEASES OF THE THYROID
→ sleep sometimes lasting 12 to 14 hours a day. 3. Increased iodination of tyrosine to form the thyroid hormones
HYPERTHYROIDISM (Toxic Goiter, Thyrotoxicosis Graves’ Disease)
EFFECT ON OTHER ENDOCRINE GLANDS 4. Increased size and increased secretory activity of the thyroid cells
• increased thyroid hormone increases the rates of secretion of all other endocrine glands • thyroid glands at least 2-3x times the normal
5. Increased number of thyroid cells
EFFECT OF THYROID HORMONE ON SEXUAL FUNCTION • change from cuboidal to columnar cells • tremendous hyperplasia
• much infolding thyroid epithelium into follicles
MEN • TH secretion = 5-15x normal
• lack of thyroid hormone = loss of libido TSH increases all known secretory activities of the thyroid glandular cells
• great excess = impotence • TSH plasma concentrations are less than normal in Graves’ disease
• most important early effect after administration of TSH
WOMEN → initiate proteolysis of thyroglobulin = release of T3 and T4 in blood within 30 minutes THYROID ADENOMA
• lack of TH = menorrhagia/polymenorrhagia (excessive/frequent menstrual bleeding) • painless tumor; develops in thyroid tissue and secretes large quantities of TH
• other women lack of TH = irreg. periods/amenorrhea (absence of menstrual bleeding) • other effects require hours or even days and weeks to develop fully
• different from usual type of hyperthyroidism
HYPOTHYROIDISM IN WOMEN CYCLIC ADENOSINE MONOPHOSPHATE MEDIATES STIMULATORY EFFECT OF TSH → not usually associated with autoimmune disease
→ greatly decreased libido • TSH binds receptors of thyroid cell
→ oligomenorrhea (greatly reduced bleeding) is common • increases cAMP formation inside cell • adenoma continues to secrete large quantities of TH
→ occasionally amenorrhea occurs → secretory function in remainder of thyroid gland almost totally inhibited
• cAMP acts as a second messenger that result in → because TH from adenoma depresses production of TSH by pituitary gland
1. immediate increase in secretion of thyroid hormones
2. prolonged growth of the thyroid glandular tissue itself SYMPTOMS OF HYPERTHYROIDISM
1. state of excitability
2. heat intolerance
ANTERIOR PITUITARY SECRETION OF TSH; REGULATED BY THYROTROPIN-RELEASING 3. increased sweating
HORMONE FROM THE HYPOTHALAMUS 4. mild to extreme weight loss
5. varying degrees of diarrhea
• Anterior pituitary secretion of TSH 6. muscle weakness
= controlled by thyrotropin release hormone from hypothalamus 7. nervousness or other psychic disorders
secreted by nerve endings in the median eminence of the hypothalamus 8. extreme fatigue, but inability to sleep
9. hand tremors
• TRH then transported to ant. pituitary by way of hypothalamic-hypophysial portal blood
*Protrusion of the eyeballs = exophthalmos
TRH • damage to vision because it scratches the optic nerve
• tripeptide amide—pyroglutamyl-histidyl proline-amide • dry and irritated eyes = not be closed completely when a person blink
• stimulates anterior pituitary gland cells to increase their output of TSH. • causes of protrusion:
• exposure to cold = best stimuli in increasing TRH → edematous swelling of retroorbital tissues
→ degenerative changes in the extra ocular muscles
• Acute decrease in secretion of TSH = excitement and anxiety (effect of CNS) • autoimmune process with high concentrations of TSI

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DIAGNOSTIC TESTS FOR HYPERTHYROIDISM
• measure free T4 (and T3) = most accurate diagnostic tests
Other tests:
• basal metabolic rate
→ when solved is increased to 30 to 60 in severe hyperthyroidism
• TSH = low in thyrotoxicosis +++increased thyroid hormones
• TSI concentration = high in thyrotoxicosis but low in thyroid adenoma
TREATMENT FOR HYPERTHYROIDISM
• Most Direct Treatment = Surgical Removal of most of thyroid gland
• Treatment of the Hyperplastic Thyroid Gland = Radioactive Iodine
→ 80% to 90% is absorbed within one day of injection
→ destroys circulatory cells
→ thyroid function is reassessed after several weeks
→ keep radioactive iodine injection until the thyroid levels are known
HYPOTHYROIDISM
• initiated by autoimmunity that destroys gland = Hashimoto's disease
→ but in this case autoimmunity destroys gland rather than stimulates
AUTOIMMUNE THYROIDITIS >>> inflammation
• inflammation causes progressive deterioration and finally fibrosis of gland
→ with diminished to absent depletion of thyroid hormones
THYROID GOITER
ENDEMIC COLLOID GOITER
• caused by dietary iodide deficiency
• endemic in mountainous areas (like Swiss Mountains)
• lack of iodine prevents production of T3 and T4 = increase TSH
→ stimulates production of thyroglobulin = gland grow 10-20x normal
IDIOPATHIC NONTOXIC COLLOID GOITER
• exact cause is unknown; but most of patients show signs of mild thyroiditis
• Thyroiditis = causes slight hypothyroidism
→ increase TSH secretion and progressive growth of noninflamed portions of gland
→ nodular = some portions are growing and other portions are destroyed by thyroiditis
ABNORMALITIES IN ENZYMES
Deficiency in:
1. Iodide Trapping Mechanism = iodine is not pumped adequately
2. Peroxidase System = iodides are not oxidized
3. Coupling of Iodinated Tyrosine in The Thyroglobulin = final TH not formed and
4. Deiodinase Enzyme = prevents recovery of iodine from iodinated
*Goitrogenic Substances = in cabbages and turnips
PHYSIOLOGICAL CHARACTERISTICS OF HYPOTHYROIDISM CRETINISM
• fatigue and extreme somnolence (sleeping up to 12 to 14 hours a day) • extreme hypothyroidism during fetal life, infancy, or childhood
• extreme muscular sluggishness → failure of body growth and mental retardation
• slowed heart rate
• decreased cardiac output • skeletal growth in a child is more inhibited than soft tissue growth
• decreased blood volume
• increased body weight • self-tissue enlarges excessively = obese, stocky, and short appearance
• constipation
• mental sluggishness • tongue = enlarge in relation to the skeletal growth
• depressed growth of hair and scaliness of skin, → obstructs swallowing and breathing
• froglike/husky voice → inducing a characteristic guttural breathing = sometimes chokes child
Severe Cases • Congenital Cretinism = congenital lack of a thyroid gland
• development of an edematous appearance throughout body = myxedema. • Endemic Cretinism = lack of iodine in the diet
MYXEDEMA *Neonate without a thyroid gland may have a normal appearance and function
• develops in persons who have almost total lack of thyroid hormone function • supplied with some by mother while in utero.
→ bagginess under eyes and swelling of the face • After birth:
→ neonate’s movements = sluggish
• greatly increased quantities of hyaluronic acid and chondroitin sulfate bound with protein → both physical and mental growth = retarded
→ form excessive tissue gel in interstitial spaces
→ causes total quantity of interstitial fluid to increase treatment of the neonate with cretinism
• adequate iodine or thyroxine usually causes normal return of physical growth
• gel nature of excess fluid = immobile
→ edema is the nonpitting type
ATHEROSCLEROSIS IN HYPOTHYROIDISM
• lack of thyroid hormone >>> increases quantity of blood cholesterol
• increase in blood cholesterol = increased atherosclerosis
• hypothyroid patients (those with myxedema) develop atherosclerosis = results in:
→ peripheral vascular disease
→ deafness
→ coronary artery disease
→ subsequent early death
DIAGNOSTIC TESTS FOR HYPOTHYROIDISM. The tests already
*diagnosis of hyperthyroidism gives opposite results in hypothyroidism
• Low T4
• Low basal metabolic rate (−30 and −50)
• Increased TSH = when test dose of TRH is administered
• Low TSH = hypothyroidism from depressed response of pituitary gland to TRH
TREATMENT OF HYPOTHYROIDISM. Figure 77-4 shows the
• daily oral ingestion of thyroxine tablets.
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